Accumulating evidence indicates that some of the many RNAs identified in body fluids and cell culture medium may be functional. Although proof-of-principle and validation projects have demonstrated cell-to-cell RNA transfer, not a single mammalian extracellular RNA has been demonstrated to enter and function in a target cell, at least in a biologically relevant and robust manner. Moreover exRNA uptake has yet to be characterized in a primary mammalian model. We do not know the functional consequences for exRNA uptake, or for that matter, the consequences of uptake deficiency. Studies over the last few years have illustrated a large and diverse population of exRNAs, including microRNA and long non-coding RNA (IncRNAs) - but we have no reference set for specific tissues, nor do we have an understanding of which exRNAs are functionally important for those tissues. Likewise, we do not have any idea of the genes involved, save for two homologs for the C. elegans SID-1 exRNA transporter that are still awaiting full characterization. Whether all, or only a few cell types can uptake exRNA also remains a complete mystery. This U19 Cooperative Agreement directly addresses critical gaps in our knowledge of the fundamental principles of exRNA biogenesis, distribution, uptake, and function.